Certain trace minerals are essential nutrients for all animals, including cattle and other ruminants. See National Research Council: xe2x80x9cNutrient Requirements of Beef Cattle xe2x80x9d, Washington DC, Natl Acad Sci, p 62-64, 1996. Such trace minerals include selenium, iodine, manganese, chromium, cobalt, copper, and zinc. Selenium, for example, is essential for the function of a number of critical mammalian selenoproteins, including for example the antioxidant enzyme glutathione peroxidase. In cattle, the selenium requirements are between 0.1 and 0.5 parts per million (ppm) of the diet on a dry matter basis. The Food and Drug Administration (FDA) has set an allowable supplementation level at 0.3 parts per million (ppm) of the diet for selenium and a maximum allowable level of supplemental selenium at 3 milligrams (mg) selenium per head per day for cattle.
Typically in cattle, selenium status is evaluated by measuring the selenium concentration in whole blood. See Maas, Diagnosis and Management of Selenium-Responsive Diseases in Cattle, 1983, Compend Contin Educ Pract Vet 5: S393-399; and Maas, The Correlation Between Serum Selenium and Blood Selenium in Cattle, 1992, J Vet Diagn Invest 4: 48-52. In cattle, blood selenium concentrations between 0.1 ppm to 1.0 ppm are considered normal, concentrations between 0.04 ppm to 0.1 ppm are considered marginally deficient, and concentrations below 0.04 ppm are considered frankly deficient. Marginally deficient blood selenium concentrations are indicative of potential subclinical disease symptoms and deficient blood selenium concentrations are indicative of potential clinical disease states. Most normal ruminants have blood selenium concentrations between 0.1 ppm and 0.3 ppm, whether or not their feed has been supplemented.
Selenium deficiency is the most commonly diagnosed disease problem in beef cattle in California. See 1997 Annual Report California Veterinary Diagnostic Laboratory System, pages 23-25, School of Veterinary Medicine, University of California, Davis (June 1998). Previous University of California studies have shown that 65% of beef cattle in Northern California and 64% of beef cattle in Central and Southern California are Selenium deficient. See Williams, 1988, xe2x80x9cA survey into selenium deficiency in cattle in Northern California. xe2x80x9d Master of Preventative Medicine Thesis. University of California, Davis. 55 pp; and Dunbar, 1988, xe2x80x9cPreliminary Report on the Survey of Selenium Whole Blood Values of Beef Herds in Twelve Central and Coastal California Countiesxe2x80x9d pages 81-83 in Selenium Contents in Animal and Human Food Crops Grown in California. Cooperative Extension, University of California Division of Agriculture and Natural Resources, Publication 3330, Oakland, Calif. Both small and large ranching operations, which use pasture grazing on a continual basis, are affected by the grazing of cattle on selenium deficient ranch lands, which are prevalent in California and most other cattle producing states. National surveys by the USDA indicate that 63.6% of forage samples are deficient or marginal for selenium. xe2x80x9cTrace mineral contents of harvested foragesxe2x80x9d, USDA:APHIS, NAHMS Survey, October, 1996. Thus, cattle relying on this selenium deficient forage would require some level of selenium supplementation. Additionally, 18.2% of cattle in the United States were selenium deficient despite supplementation or producer""s knowledge of supplementation methods. xe2x80x9cBlood selenium levels in the U.S. beef cow/calf herd.xe2x80x9d USDA:APHIS, NAHMS Survey, October, 1996. In a survey of state veterinarians and state veterinary diagnostic laboratories, selenium-deficiency diseases were reported in 46 states and selenium deficiencies were reported to be an important livestock problem in 37 states. See, A. J. Edmondson, et al, xe2x80x9cSurvey of state veterinarians and state veterinary diagnostic laboratories for selenium deficiency and toxicosis in animalsxe2x80x9d Journal of the American Veterinary Medical Association, Vol. 202 (6), pp. 865-872, 1993. Thus, selenium supplementation continues to be necessary for the health, welfare, and productivity of grazing cattle in the United States.
Selenium deficient cattle typically exhibit decreased weight gains, decreased feed efficiency, chronic diarrhea, nutritional myodegeneration (white muscle disease), increased spontaneous abortion rates, reproductive losses due to retained placenta, illthrift, decreased immune function and increased susceptibility to infectious diseases. See Maas, Diagnosis and Management of Selenium-Responsive Diseases in Cattle, 1983, Compend Contin Educ Pract Vet 5: S393-S399. Cattle affected with trace mineral deficiencies, such as selenium deficiency, often have symptoms that mimic infectious or parasitic diseases and conditions such as diarrhea, lameness and illthrift. Commonly, animals with trace mineral deficiencies, such as selenium deficiency, are erroneously treated symptomatically by administration of antibiotics, parasiticides or other drugs that could leave residues in tissues.
Because of these conditions, the economic efficiency of raising cattle deficient in selenium or other trace minerals is decreased compared to raising cattle that are not deficient. For example, increased susceptibility to infectious diseases caused by lowered immune system function due to trace mineral deficiencies results in the increased use of antibiotics in animal health and production, which in turn has an adverse affect on profitability.
In the past, various methods have been used to increase the amount of trace minerals in animal diets. Animals confined in feeding operations such as poultry units, feedlots or dairies typically receive a formulated or mixed ration supplemented with the trace minerals required. Free ranging animals, those that graze on range lands, in foothill pastures, and on permanent pasture lands, for example, cannot obtain needed supplemental selenium or other trace minerals in this manner because it is cost prohibitive and impractical. Currently, salt-mineral mixes are employed to give grazing cattle supplemental dosages of selenium. The disadvantage to this approach is that it can often result in unpredictable and sporadic dosing, because the cattle can choose to ingest the mix, and also because of varying pasture conditions and varying climatic and seasonal conditions such as temperature and precipitation variations throughout the year. In addition, salt-mineral mixes are expensive due to labor costs and manufacturing costs.
Trace minerals have been administered to cattle by injection, but there are demonstrated limitations on the effectiveness of this method. For example, studies have shown that selenium administered by injection results in rapid increases in blood selenium concentration of very short duration, i.e., less than 45 days, and only partially meet the animals selenium nutrient requirements. See, Maas, et al, xe2x80x9cIntramuscular selenium administration in selenium-deficient cattle.xe2x80x9d Journal of Veterinary Internal Medicine, vol. 7, pp.342-348, 1993.
Boluses are solid, ingredient release systems for oral administration in ruminants. The bolus remains in the gastrointestinal tract of the animal due to either its geometric shape or its density and mass. Boluses have been employed previously to deliver therapeutics, mineral supplements and a variety of other active ingredients to ruminants. For example, U.S. Pat. No. 4,765,837 issued Aug. 23, 1998 discloses a bolus for administration to a ruminant comprising a magnesium-based alloy and optionally trace elements including selenium up to 1% by weight. U.S. Pat. No. 4,044,119 issued Aug. 23, 1977 discloses an oral dosage medicinal composition for ruminants made by treating an admixture of milk solids and the medicament with an aldehydic agent to insolubilize the milk protein solids, granulating the product and compressing the granules under sufficient pressure to form a densified body having a specific gravity at least greater than about 1. U.S. Pat. No. 4,671,789 issued Jun. 9, 1987 discloses a controlled release composition for administering therapeutics to ruminants comprising a compressed bolus including the therapeutic and a non-tacky, free-flowing powdered, carrier material comprising a sucrose ester, polyglyceryl stearate or milk powder. U.S. Pat. No. 4,662,879 issued May 5, 1987 discloses a bolus composed of water soluble glass incorporating the mineral supplement contained in a plastic housing. U.S. Pat. No. 4,251,506 issued Feb. 17, 1981 discloses a controlled release composition for administering active ingredients to ruminants comprising the active agent in a matrix of water insoluble wax and at least two surfactants having an HLB value of 8.5 or less to avoid differential dissolution and non-uniform active agent release. U.S. Pat. No. 5,252,561 issued Oct. 12, 1993 discloses a controlled release bolus comprising the active ingredient, a wax, a weighting agent and a sugar, sugar alcohol, cellulose ether or a polyethylene glycol. U.S. Pat. No. 4,765,837 issued Aug. 23, 1988 discloses a bolus composes of compressed magnesium, zinc, and aluminum. U.S. Pat. No. 4,595,583 issued Jun. 17, 1986 discloses a bolus for the administration of a beneficial agent to ruminants, which comprises an osmotic pump with a semi-permeable membrane. U.S. Pat. No. 5,985,314 issued Nov. 16, 1999 discloses a bolus comprising a rosin matrix in which the active ingredient is dispersed and a non-soluble ballast material such as iron bound in the rosin matrix.
In addition, an iron-based, slow-release, selenium pellet made by Imperial Chemical Industries, Australia and called xe2x80x9cPermaselxe2x80x9d was in use in the United States (specifically California) from about 1980 to 1992. See, Wilson, Evaluation of Multiple Reticulorumen Selenium Pellets as a Health Risk in Growing Hereford Steers, 1991, Am J Vet Res 55: 247-50. These xe2x80x9cPermaselxe2x80x9d pellets exhibited unpredictable, inconsistent, wide variations in selenium release and they readily broke apart after manufacture and prior to use, for example, either during shipment or during storage, rendering them unusable. In addition, the Permasel pellets released daily concentrations of selenium in excess of those amounts approved by United States federal and state regulatory authorities, specifically, greater than 3 mg selenium per head per day.
It would be advantageous to provide a trace mineral supplement in bolus form for range and pasture managed cattle that is safe, capable of consistently providing the requisite amount of the trace mineral up to the regulated maximum and maintaining its form during transit and storage prior to use and is cost effective and practical for cattle ranchers to use. It would be particularly advantageous to provide a selenium supplement in bolus form that could accomplish the foregoing.
It has been found that to obtain consistent and predictable release of trace minerals, in particular selenium, from solid boluses, four variables must be evaluated and integrated. The four variables are: (1) the concentration of the trace mineral, (2) the particle size of the trace mineral, (3) the pressure under which the bolus is formed, and (4) the surface area of the bolus, which is a function of the size and shape of the bolus.
Surprisingly, it has been found that consistent and reliable release of selenium up to the regulated maximum limit can be achieved when the bolus comprises particulate selenium in concentrations of between 2% and 25% by weight and having an average diameter from 20 microns to 1,500 microns combined under 2,000 to 50,000 pounds per square inch (psi) with an inert metal powder to form a bolus having a mass of between 10 to 50 grams and a final bolus size between 10 mm and 40 mm in diameter and between 10 mm and 30 mm in height and a final density of 6.1 to 6.4 g/cm3. It has been found that boluses having the foregoing characteristics will release a consistent, reliable amount of selenium in an amount not greater than 3 mg per head per day. In addition, in has been found that such boluses maintain their shape after manufacture and do not break apart prior to use, for example during transit or storage.
Accordingly, in one aspect, the invention relates to a bolus for oral administration of selenium to ruminants comprising a solid, compressed dosage form composed of about 2% to about 25% by weight of selenium in particulate form, about 70% to about 97.5% by weight of an inert, powdered, weighting agent and optionally about 0.25 to about 5% by weight of an inert lubricant. Preferably, the selenium. comprises from about 5 to about 15% by weight, most preferably from about 8 to about 12% by weight. The particulate selenium should have an average diameter in the range of 20 to 1,500 microns, most preferably in the range of 70 to 500 microns, when combined with the inert, powdered weighting agent under between 2,000 and 50,000 pounds per square inch (psi) to form the bolus. The mass of the bolus should be in the range of about 10 to about 50 grams, preferably in the range of about 25 to about 35 grams, most preferably about 30 grams. The size of the bolus should be in the range of 10 to 40 millimeters (mm) in diameter and in the range of 10 and 30 mm in height, more preferably in the range of 15 to 25 mm in diameter and in the range of 15 to 25 mm in height, and, most preferably, approximately 20mm in diameter and approximately 16.5 mm in height. The selenium particles should have an average diameter in the range of about 70 to about 500 microns when combined with inert metal powder under about 18,000 to about 25,000 psi, given a size range from 25 to 35 grams (g) and a final density in about 6.1 to about 6.4 g/cm3. Table 1 below sets forth the range of specifications for the particular boluses of the invention.
By ruminant, I mean, in particular, cattle, sheep and goats. By xe2x80x9cdosage formxe2x80x9d, I mean a form that results in release of the active ingredient in a consistent and reliable dosage. In shape, the bolus can be spherical, cylindrical, elongated cylindrical, flat cylindrical or donut. Each of these shapes, having heights and diameters in the ranges set forth, will provide the requisite surface area to release the selenium active ingredient in an amount not greater than 3.0 mg per head per day.
Inert powdered weighting agents include those that have a density high enough to maintain the bolus in the stomach, despite the animal""s natural regurgitation mechanisms. Such density depends on the size of the bolus and its surface area and the composition of the density-imparting weighting agent. Generally, a density of at least about 3.0 g/cm3 is required to maintain the bolus in the ruminant""s stomach. Accordingly, exemplary powdered weighting agents comprising, for example, nickle, tin, hydroxyapatite, barium sulfate, barium titanate, tin oxide, iron silicate, iron oxides, sponge iron, atomized base iron, stainless iron, alloyed base iron and calcium phosphates, all of which have specific densities of at least about 3.0 g/cm3 can be employed. Preferred weighting agents are powdered metals. Particularly preferred weighting agents include iron, sponge iron, or powdered metal iron particles, for example Ancorsteel 1000B(copyright) (Hoeganaes, Riverton, N.J.).
In the choice of weighting agents, particulate size is not a critical parameter. The weighting agent should have a density high enough to maintain the bolus in the animal""s stomach, generally at least about 3.0 g/cm3, and should be able to mix well with the elemental selenium and with any optional lubricant added. Such optional lubricants will now be described.
Optionally, an inert, biologically acceptable material may be included as a lubricant to aid in the formation of the bolus during manufacture. Exemplary inert biological materials include surfactants, such as Tween 80, zinc stearate, sodium lauryl sulphate, EBS, and other waxes such as Acrawax C(copyright) (N,Nxe2x80x2-ethylenebisstearamide. Acrawax C(copyright) is appropriately used in concentrations from 0.25 to 5% in the final mixture. The concentration of other lubricants should likewise range from 0.25 to 5% in the final mixture.
In another aspect, the invention comprises a method of treating ruminants with a selenium supplement comprising orally administering to the ruminant a bolus having about 2% to about 25% by weight of the trace mineral selenium in particulate form, about 70% to about 98% by weight of an inert powdered weighting agent, and optionally, about 0.25 to about 5% by weight of an inert lubricant.
In yet another aspect, the invention comprises a process for the preparation of a trace mineral bolus for oral administration in ruminants containing about 2% to about 25% by weight of selenium, about 70 to about 98% by weight of an inert powdered weighting agent and about 0.25% to about 5% of an inert, biologically acceptable lubricant. The method comprises mixing the trace mineral with the weighting agent and, optionally, the lubricant in a suitable mixer, for example a double cone mixer, or alternatively a double bell mixer, and applying to the mixture pressure in the range of about 2,000 to about 50,000 psi until a solid mass is formed. Suitable tools for applying pressures in the range specified include a 45 ton Dorst compacting press. Other appropriate tools for mixing the components and for applying pressure in the requisite range to form the bolus are well known to those of skill in the art.